Endogenous Glucocorticoids and Bone

While the adverse effects of glucocorticoids on bone are well described, positive effects of glucocorticoids on the differentiation of osteoblasts are also observed. These paradoxical effects of glucocorticoids are dose dependent. At both physiologicaland supraphysiological levels of glucocorticoids, osteoblasts and osteocytes are the major glucocorticoid target cells. However, the response of the osteoblasts to each of these is quite distinct. At physiology levels, glucocorticoids direct mesenchymal progenitor cells to differentiate towards osteoblasts and thus increase bone formation in a positive way. In contrast with ageing, the excess production of glucocorticoids, at both systemic and intracellular levels, appear to impact on osteoblast and osteocytes in a negative way in a similar fashion to that seen with therapeutic glucocorticoids. This review will focus on therole of glucocorticoids in normal bone physiology, with particular emphasis on the mechanism by which endogenous glucocorticoids impact on bone and its constituent cells.

Osteoblastic glucocorticoid signaling exacerbates high-fat-diet-induced bone loss and obesity

Chronic high-fat diet(HFD)consumption not only promotes obesity and insulin resistance,but also causes bone loss through mechanisms that are not well understood.Here,we fed wild-type CD-1 mice either chow or a HFD(43%of energy from fat)for 18 weeks;HFD-fed mice exhibited decreased trabecular volume(-28%)and cortical thickness(-14%)compared to chow-fed mice.In HFD-fed mice,bone loss was due to reduced bone formation and mineral apposition,without obvious effects on bone resorption.HFD feeding also increased skeletal expression of sclerostin and caused deterioration of the osteocyte lacunocanalicular network(LCN).In mice fed HFD,skeletal glucocorticoid signaling was activated relative to chow-fed mice,independent of serum corticosterone concentrations.We therefore examined whether skeletal glucocorticoid signaling was necessary for HFD-induced bone loss,using transgenic mice lacking glucocorticoid signaling in osteoblasts and osteocytes(HSD2^(OB/OCY)-tg mice).In HSD2^(OB/OCY)-tg mice,bone formation and mineral apposition rates were not suppressed by HFD,and bone loss was significantly attenuated.Interestingly,in HSD2^(OB/OCY)-tg mice fed HFD,both Wnt signaling(less sclerostin induction,increased P<atenin expression)and glucose uptake were significantly increased,relative to diet-and genotype-matched controls.The osteocyte LCN remained intact in HFD-fed HSD2^(OB/OCY)-tg mice.When fed a HFD,HSD2^(OB/OCY)-tg mice also increased their energy expenditure and were protected against obesity,insulin resistance,and dyslipidemia.Therefore,glucocorticoid signaling in osteoblasts and osteocytes contributes to the suppression of bone formation in HFD-fed mice.Skeletal glucocorticoid signaling is also an important determinant of glucose uptake in bone,which influences the whole-body metabolic response to HFD.

Arthritis and the role of endogenous glucocorticoids

Rheumatoid arthritis and osteoarthritis,the most common forms of arthritis,are chronic,painful,and disabling conditions.Although both diseases differ in etiology,they manifest in progressive joint destruction characterized by pathological changes in the articular cartilage,bone,and synovium.While the potent anti-inflammatory properties of therapeutic(i.e.,exogenous)glucocorticoids have been heavily researched and are widely used in clinical practice,the role of endogenous glucocorticoids in arthritis susceptibility and disease progression remains poorly understood.Current evidence from mouse models suggests that local endogenous glucocorticoid signaling is upregulated by the pro-inflammatory microenvironment in rheumatoid arthritis and by aging-related mechanisms in osteoarthritis.Furthermore,these models indicate that endogenous glucocorticoid signaling in macrophages,mast cells,and chondrocytes has anti-inflammatory effects,while signaling in fibroblast-like synoviocytes,myocytes,osteoblasts,and osteocytes has pro-inflammatory actions in rheumatoid arthritis.Conversely,in osteoarthritis,endogenous glucocorticoid signaling in both osteoblasts and chondrocytes has destructive actions.Together these studies provide insights into the role of endogenous glucocorticoids in the pathogenesis of both inflammatory and degenerative joint disease.

Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt/β-catenin signaling

Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihydroxy-vitamin D [1,25（OH）2D] are mediated through binding to the vitamin D receptor （VDR）. Here, we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad （MDA-MB-231）, subcutaneously （PC3） or intra-tibially （both cell lines） in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls. These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/0-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1, interleukin-6 （IL-6）, and IL-8. Stabilization of 0-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer.